Neonatal herpes continues to be the most devastating consequence of genital herpes infections, with a frequency that has not declined in the last several decades. Yet no prevention strategies have been implemented. The risk of HSV transmission is highest among women who have newly acquired HSV-2 or HSV-1 in the genital tract and who are seronegative; the risk is also high among HSV-1 seropositive women who have newly acquired HSV-2 or reactivation of HSV-1; the risk is low in women with established HSV-2 infection. Genital HSV shedding at the time of delivery is associated with a relative risk of >300 for HSV transmission. We have developed a sensitive and specific HSV DMA PCR that can be resulted within 2 hours of obtaining the sample; the test is completing validation studies for implementation for routine use in the University of Washington Hospital Clinical Laboratories. We propose to use this assay to develop a strategy to detect the infant exposed to HSV at delivery and to evaluate the feasibility of implementing interventions to reduce the risk of HSV-1 and HSV-2 infections in the exposed newborns. Specific Aim 1 is to determine the incidence of exposure of the neonate to HSV at the time of delivery. We hypothesize that HSV DMA detection by PCR, in combination with HSV serologic testing (performed routinely in pregnant women at the University of Washington), will accurately define HSV-exposed infants at high versus low risk of developing neonatal herpes. This information will be utilized by the medical team to reduce the risk of HSV infection either through obstetrical practices (C-section, reduced use of fetal monitoring devices, use of IV acyclovir) or subsequent management of the HSV exposed infant. Specific Aim 2 will evaluate the feasibility of intrapartum intravenous acyclovir, followed by oral acyclovir to the neonate, as an approach for managing HSV-2 seropositive women who shed HSV at delivery and their infants who are exposed to HSV during birth. We hypothesize that IV acyclovir given to women in labor will result in therapeutic levels of acyclovir in the cord blood, and that oral administration of acyclovir to the newborn will be feasible, as evaluated by clinical and laboratory measures, and acceptable to pediatricians and parents. This approach shifts the current paradigm for prevention of neonatal herpes from the women with clinical disease to the detection and management of the infant exposed to subclinical infection at delivery. The project will for the first time collect data on current American Academy of Pediatrics guidelines for HSV exposed infants and develop tools for prevention of neonatal HSV that can be tested in multicenter trials. Neonatal herpes is a serious disease among newborns. The project will develop tools to identify newborns exposed to HSV at birth at risk and develop optimal care for newborns who are at risk for neonatal herpes.